Abstract
The elderly are characterized by mucosal immunosenescence and high rates of morbidity and mortality associated with infectious diseases of the intestinal tract. Little is known about how the differentiation of immunoglobulin A (IgA) plasma cells in Peyer's patches (PPs) and their subsequent homing to the small intestinal lamina propria (LP) is affected by aging. Quantitative immunohistochemical analyses demonstrated a 2-fold increase in the number of IgA+ cells in the PPs, coupled with significant declines in the numbers of IgA+ and antibody-positive cells in the intestinal LP of senescent rats compared to young adult animals. These data suggest that aging diminishes the emigration of IgA immunoblasts from these lymphoid aggregates, as well as their migration to the intestinal LP. Flow cytometry and lymphocyte adoptive transfer studies showed 3- to 4-fold age-related declines in the homing of antibody-containing cells and mesenteric lymph node lymphocytes to the small intestines of rhesus macaques and rats, respectively. The number of peripheral blood IgA immunoblasts expressing the homing molecule α4β7 declined 30% in senescent rats. This was accompanied by a >17% decrease in the areal density of LP blood vessels staining positive for the cell adhesion molecule MAdCAM-1. Cumulatively, declines in expression of these homing molecules constitute a substantial age-related diminution of IgA immunoblast homing potential. In vitro antibody secretion by LP plasma cells, i.e. antibody secreted per antibody-positive cell, remains unchanged as a function of donor age. Intestinal mucosal immunosenescence is a consequence of reduced homing of IgA plasma cells to the intestinal LP as a result of declines in homing molecule expression.
Highlights
Intestinal Mucosal Immune SystemMucosal surfaces constitute a discrete compartment of the immune system by virtue of a different immunoglobulin isotype, a unique process for generating an immune response and an independent lymphocyte subpopulation
We demonstrated that the in vitro secretion of anti-cholera toxin (CTx)-immunoglobulin A (IgA) antibodies by lymphocytes isolated from the intestinal lamina propria (LP) of senescent rats is significantly lower (. 60%) than that of similar cells obtained from young animals (Thoreux et al, 2000; Fig. 4)
We recently showed that 1028 M CCK enhances in vitro anti-CTx IgA secretion by LP lymphocytes isolated from young adult and senescent rats by,140% in comparison to their respective nonstimulated age cohorts
Summary
Mucosal surfaces constitute a discrete compartment of the immune system by virtue of a different immunoglobulin isotype (immunoglobulin A, IgA), a unique process for generating an immune response and an independent lymphocyte subpopulation. 400 m2 of mucosal surface available for antigen uptake; it contains . 70% of an organism’s plasma cells and it produces more IgA than the organism’s production of immunoglobulin G (IgG). Mucosal surfaces are the first line of immune defense and IgA antibodies neutralize toxins, block the adherence of bacteria to the epithelium and reduce the penetration of antigens across the mucosa. An effective response in the intestine involves: (1) binding, uptake, transport of antigen at the mucosal surface, antigen presentation by dendritic cells or macrophages within the Peyer’s patches (PPs) and IgA isotype switching, (2) maturation and homing of antigenstimulated PP IgA B immunoblasts to the intestinal lamina propria (LP), (3) local antibody production by mature IgA plasma cells in the LP and (4) transport of IgA antibodies across the intestinal epithelium to the mucosal surface by pIg receptor. Diminished intestinal IgA antibody titers in the elderly may reflect age-associated deficits in one or more of these critical events
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